Analysis of real-world outcomes of <i>IKZF</i><sup>mut</sup> in Philadelphia chromosome-positive ALL: A retrospective, single-institution experience.
Authors: Kyle Zacholski, Ian Michael Bouligny, Chad Michael Venn, Valerie Tran, Yanal Mufeed Alnimer, Thuy Ho, Keri Renee Maher
Journal: Journal of Clinical Oncology (2022)

e19032 Background: Presence of the Philadelphia chromosome (Ph+) or IKZF mut is associated with a poor prognosis in B-cell ALL. The clinical impact of both mutations occurring together in adult patients is currently unknown. We sought to analyze outcomes of patients with Ph+ B-ALL and IKZF mut treated with induction with TKI-based regimens outside of the context of clinical trials. Methods: We identified 10 patients with Ph+ B-ALL treated at our institution during January 2015 to January 2021 that had IKFZ mut identified through NGS. Seven had IKFZ mut at the time of diagnosis and three acquired IKFZ mut at the time of relapse. Baseline patient demographics were obtained, including age, performance status and comorbidities at diagnosis, cytogenetic and molecular profiling through NGS, doses of induction, toxicity, response, measurable residual disease (MRD) analysis, and survival, and incidence of relapse. The event for calculating the overall survival (OS) was the date of death and patients were otherwise censored at the date of last contact. Results: The median age of the 7 patients IKFZ mut with at diagnosis was 58 years (range: 44 - 72), 57.1% were male, the median ECOG score was 1 (range: 1 - 3), and the median Charlson Comorbidity Index score was 4. Other commonly occurring mutations were ABL1 (42.9%), with CDKN2A, ETV6, and PTPN11 occurring at 14.3% each. Dasatinib was the most common TKI given in 85.7% of patients in combination with hyperCVAD (42.9%), EWALL-Ph-01 (28.6%), ECOG 1910 (14.3%), and ECOG 2993 (14.3%). In total, 71.4% achieved CR, with 50.0% in CR by MRD. Two patients received allogeneic stem cell transplant (HSCT) and 28.6% had relapsed or refractory disease by 1.2 years. At a median follow-up time of 1.7 years, the median survival was not reached. Three additional patients were found to have IKZF mut at the time of relapse or refractory disease. The median age was 38 years, 2 (66.6%) had a co-occurring mutation in ABL1, and all were treated with dasatinib at time of salvage, two in combination with hyperCVAD and one with EWALL-Ph-01. There were no deaths during induction and two patients had evaluable responses and both achieved CR, and one by MRD. Conclusions: To the best of our knowledge, these are among the first of limited reports regarding outcomes of adult patients with Ph+ B-ALL and IKZF mut . Although the cohort is limited by sample size due to the rarity of the co-occurring mutations, the response rates appear to be numerically similar in upfront treatment of Ph+ and IKZF mut compared to historical data for Ph+ B-ALL alone in the era of TKIs. Gain of IKZF mut may be a sign of clonal evolution of disease, and further work to elucidate prognostic implications in the relapsed and refractory group is warranted. Larger prospective, randomized studies investigating differential responses to modern combinatorial chemoimmunotherapy + TKI approaches are warranted in this population.